Inflammatory bowel disease and COVID-19 outcomes: a meta-analysis

There is conflicting evidence concerning the effect of inflammatory bowel disease (IBD) on COVID-19 incidence and outcome. Hence, we aimed to evaluate the published evidence through a systematic review process and perform a meta-analysis to assess the association between IBD and COVID-19. A compressive literature search was performed in PubMed/Medline, Scopus, Embase, and Cochrane Library from inception to July 2021. A snowball search in Google, Google Scholar, Research Gate, and MedRxiv; and bibliographic research were also performed to identify any other relevant articles. Quantitative observational studies such as cohort, cross-sectional, and case–control studies that assessed the incidence, risk, and outcomes of COVID-19 among the adult IBD patients published in the English language, were considered for this review. The incidence and risk of COVID-19, COVID-19 hospitalization, the severity of COVID-19, and mortality were considered as the outcomes of interest. The Joanna Briggs Institute critical appraisal checklist was used for quality assessment. A subgroup and sensitivity analysis were performed to explore the heterogeneity and robustness of the results, respectively. A total of 86 studies out of 2828 non-duplicate records were considered for this meta-analysis. The studies were single or multicentric internationally from settings such as IBD centres, medical colleges, hospitals, or from the general public. Most of the studies were observed to be of good quality with an acceptable risk of bias. The pooled prevalence of COVID-19, COVID-19 hospitalization, severe COVID-19, and mortality in the IBD population were 6.10%, 10.63%, 40.43%, and 1.94%, respectively. IBD was not significantly (p > 0.05) associated with the risk of COVID-19, COVID-19 hospitalization, severe COVID-19, and mortality. In contrast, ulcerative colitis was significantly associated with a higher risk of COVID-19 (OR 1.37; p = 0.01), COVID-19 hospitalization (OR 1.28; p < 0.00001), and severe COVID-19 (OR 2.45; p < 0.0007). Crohn’s disease was significantly associated with a lesser risk of severe COVID-19 (OR 0.48; p = 0.02). Type of IBD was a potential factor that might have contributed to the higher level of heterogeneity. There was a significant association between ulcerative colitis and increased risk of COVID-19, COVID-19 hospitalization, and severe COVID-19 infection. This association was not observed in patients with Crohns' disease or in those diagnosed non-specifically as IBD.

Risk of bias and quality assessment. The Joanna Briggs Institute critical appraisal checklist was used to assess the methodological quality and risk of bias of included prevalence studies, cross-sectional studies, casecontrol studies and cohort studies 20 . The Joanna Briggs appraisal for prevalence studies addresses the appropriateness of sample frame, study participants, sample size, measure of condition, study setting, data analysis, and response rate. The checklist for cross-sectional studies assessed study aspects such as inclusion criteria, study subjects and setting, measure of exposure, measurement of the condition, confounding factors, outcomes measurement, and the statistical analysis used. The checklist for the case-control studies assessed study aspects such as comparability and matching of population, participant criteria, measurement of exposures, confounding factors, strategies to deal with confounding factors, outcome measurement, follow-up time, and statistical analysis Characteristics of included studies. Among the included studies, 50 studies (58.1%) were published in 2021 and 36 studies (41.9%) in 2020. The majority of studies emerged from the USA (30.23%; n = 26), followed by Italy (20.93%; n = 18), Spain (13.95%; n = 12), Denmark (3.49%; n = 3), France (3.49%; n = 3), the United Kingdom (3.49%; n = 3) Germany (2.32%; n = 2), Iran (2.32%; n = 2), Israel (2.32%; n = 2), and Norway (2.32%; n = 2). The remaining studies were from countries such as Chile (1.16%; n = 1), Egypt (1.16%; n = 1), China (1.16%; n = 1), France & Italy (1.16%; n = 1), India (1.16%; n = 1), Italy & Germany (1.16%; n = 1), Netherlands (1.16%; n = 1), Poland (1.16%; n = 1), Romania (1.16%; n = 1), Saudi Arabia (1.16%; n = 1), Serbia (1.16%; n = 1), and Sweden (1.16%; n = 1); information regarding the country was not available from one study (1.16%; n = 1) as it was a conference abstract. The studies included were single or multi centre; national or international; retrospective or prospective cohort studies, population-based cohort studies, case-control studies, registry analysis, and direct or web-based cross-sectional studies. A total of 34,059,455 participants were included among the studies, out of which 814,633 were IBD patients. The data were collected from IBD centres, medical colleges, hospitals or from the general public. A detailed assessment of characteristics for each included study is illustrated in Table 1.
Visual inspection of funnel plot observed an obvious asymmetry ( Supplementary Fig. S3A) indicating the chances of publication bias which was confirmed by Begg's test (p = 0.014), but not with Egger's test (p = 0.087). A sensitivity analysis by removing a study by Singh et al. 99 indicated no much difference from the overall pooled estimate (6.07%; 95% CI 3.09-9.06%; 62 studies). The result is provided in Supplementary Fig. S4A.
Visual inspection of funnel plot does not show an obvious asymmetry which is suggestive no publication bias ( Supplementary Fig. S3B) which was further confirmed by Egger's (p = 0.999) and Begg's test (p = 0.649). A sensitivity analysis by removing single study by Grunert et al. 105 57,76 recorded the COVID-19-related hospitalization rate in patients with CD and UC separately, which was 9.43% (95% CI − 7.90 to 26.75%) and 11.85% (95% CI − 9.25, www.nature.com/scientificreports/ 32.95%), respectively. No change was in heterogeneity was observed after subgroup analysis based on the type of IBD (Fig. 4). Visual inspection of funnel plot observed an obvious asymmetry suggestive of publication bias (Supplementary File S3C) which was not confirmed through Egger's (p = 0.907) and Begg's (p = 0.252) test. A sensitivity analysis by removing single study estimated no much changes in actual results (10.94; 95% CI 6.92, 14.96; 31 studies). The results are provided in Supplementary File S4C.
The subgroup analysis recorded a significantly higher risk of COVID-19-related hospitalization in UC patients (OR 1.28; 95% CI 1.19-1.38; p < 0.00001; n = 4 studies) compared to non-UC patients 27,50,57,94 . However, CD (OR 0.94; 95% CI 0.84-1.06; p = 0.32; n = 2 studies) 48,50 and MC (OR 1.28; 95% CI 0.95-1.72; p = 0.11; 1 study) 60 was not significantly associated with risk of COVID-19 associated hospitalization. There was a non-significant heterogeneity after the subgroup analysis based on the type of IBD such as CD and UC (I 2 : 0%). This indicates that type of IBD might be a significant factor that contributed to the variation observed among the study findings (Fig. 5).

Severity of COVID-19 in patients with IBD.
The visual inspection of funnel plot observed an obvious asymmetry (Supplementary File S3E) suggestive of publication bias which was confirmed by Egger's (p = 0.025) and Begg's (p = 0.0002). The sensitivity analysis was not performed for this analysis.
Risk of severe COVID-19 in patients with IBD. A summary estimate of 9 studies 30,31,63,77,79,83,94,99,101 indicated no association between IBD and severe COVID-19 (OR 1.05; 95% CI 0.73-1.49; p = 0.80) compared to non-IBD patients. A substantial level of heterogeneity (I 2 : 66%) was observed, hence random effect model was applied.   30 . The heterogeneity observed in the overall analysis was not observed in subgroup analysis based on the type of IBD such as CD and UC (I 2 : 0%). This indicates that type of IBD might be a significant factor that contributed to the variation observed among the study findings (Fig. 7).
Subgroup analysis indicates that, a single study 76 reported mortality rate of 0.14% (95% CI − 1.82 to 2.10%) in CD patients and an estimate of 3 studies 26,57,76 indicated a mortality rate of 2.79% (95% CI 0.60-4.99%) in patients with UC. The subgroup analysis based on the type of IBD did not alter the level of heterogeneity indicative of its non-contribution in heterogeneity (Fig. 8).
The visual inspection of funnel plot observed no obvious asymmetry (Supplementary File S3F) which is suggestive of no publication bias which was confirmed by Egger's (p = 0.348) and Begg's (p = 0.881). A sensitivity analysis by removing the study by Axelrad et al. 67 indicated no changes in overall results (OR 1.90; 95% CI 1.30-2.62). The result is provided in Supplementary File S4F.
The visual inspection of funnel plot observed no obvious asymmetry (Supplementary File S3H) which is suggestive of no publication bias which was confirmed by Egger's (p = 0.849) and Begg's (p = 0.881) (Fig. 10). A sensitivity analysis by removing the study by Maconi et al. 13 indicated no changes in overall results (OR 2.29; 95% CI 0.75-6.94). The result is provided in Supplementary File S4G.

Discussion
As there is conflicting evidence with respect to the incidence of COVID-19 in patients with IBD, the currently available guidelines for IBD management support the continuation of the use of biologics such as tofacitinib, ustekinumab, and vedolizumab 108 . Moreover, existing evidence fails to establish a positive association between the use of biologics or immunosuppressives with the risk of COVID-19 79 . Additionally, biologics use was associated with a lower risk of COVID-19 hospitalization, intensive care unit admission, and mortality among IBD patients 107 . Most of the studies were from the USA, Italy, and Spain, and the remaining countries were observed to have a lesser number of studies from an IBD population. This is an indication of underreporting, which might be due to a lack of manpower or test kits, and other barriers to access the data and patients 107 .
The findings from the current meta-analysis indicate an overall prevalence of 6.10% (95% CI 3.15-9.04%) of COVID-19 in patients with IBD. Moreover, a significant association could not be identified from the risk estimate (OR 1.15; 95% CI 0.97-1.37; p = 0.11). Similarly, a previous meta-analysis by Singh et al., suggested no difference in risk of COVID-19 in IBD patients when compared to the general population 107 . However, their findings with regards to the association between the risk of COVID-19 and type of IBD differed from our observation. They recorded a non-significant risk in both CD and UC patients, whereas our analysis showed a significantly higher risk in UC patients (OR 1.37; 95% CI 1.07-1.74; p = 0.01). This might be due to the single comparison group that was used by Singh et al., which is the general population. Interestingly, the meta-analysis of 14 studies performed by Tripathi et al., recorded a similar observation in which they recorded a very low incidence (1.01%) of COVID-infection in IBD cohort. Their therapy based analysis revealed a significantly poorer outcomes among www.nature.com/scientificreports/ those on corticosteroids or mesalamine, though anti-TNFs group had a better outcomes 108 . These findings were strengthened by another meta-analysis conducted by Alrashed et al. 109,110 . They also posed a higher risk with other management such as 5-aminosalicylic acid. However, use of vedolizumab, tofacitinib, and immunomodulators alone or in combination with anti-TNF were not associated with severe disease, rather anti-TNFs, and ustekinumab had a better outcomes. The reported COVID-19 hospitalization rate was 10.63% (95% CI 6.67-14.60%) in patients with IBD, which was lesser in the CD (9.43%; 95% CI − 7.90 to 26.75%) and higher in UC (11.85%; 95% CI − 9.25, 32.95%) subtypes, respectively. A similar trend was observed with the risk of COVID-19 hospitalization, where a non-significant association was found in the overall IBD population (p = 0.50), CD (p = 0.32), and MC (p = 0.11) patients. Moreover, the risk of COVID-19 hospitalization was significantly higher among patients with UC (p < 0.00001). The severe nature of disease, high level of immunosuppression, and higher hospitalization rate might have contributed to a significantly higher rate of COVID-associated hospitalization and severity in patients with UC than CD 107,111 . We could observe through our meta-analysis that 7.95% and 2.86% of IBD patients had mild and moderate disease, though a higher percentage (40.43%; 95% CI 0.05-31,869.21%) had severe COVID-19. A non-significant association was observed between severe COVID-19 and IBD (p = 0.80), MC (p = 0.09) and IBD-U (p = 0.47). In contrast, a significantly lesser risk was observed in CD patients (OR 0.48; p = 0.02) and significantly higher risk in UC patients (OR 2.45; p < 0.0007). Along with the nature of the disease, factors such as advanced age of ≥ 65 years 72,79 , unvaccinated status 89 , CC subtype, use of oral steroids and proton pump inhibitors, rs13071258 A variant 63 , female gender, obesity, and concomitant diseases such as diabetes, hypertension, and asthma 79 were associated with a higher risk of severe COVID-19 in IBD patients.
The pooled mortality rate was found to be 1.94%, 0.14%, and 2.79% in IBD, CD, and UC patients respectively. A non-significant association was observed between the COVID-19 mortality and IBD (p = 0.13) and subtypes such as CD (p = 0.14) and UC (p = 0.09). Comparatively, studies by Bezzio et al. (OR 8.45) 11 , and Ludvigsson et al. (OR 1.92) 77 recorded significantly higher mortality in IBD patients. Similarly, Xu et al. 50 and Bezzio et al. 11 recorded significantly higher mortality in CD (OR 19.93) and UC (OR 22.65) patients, respectively. The evidence indicates that many other factors, such as the use of biologics 12 , advanced age 11,42,95 , active IBD status, www.nature.com/scientificreports/ higher Charlson comorbidity index score 11 , comorbidities, use of corticosteroids 48,101,112 and thiopurines 101 were significantly associated with COVID-19 mortality in the IBD population. Very recent evidence also indicates a non-significant effect of corticosteroids in mortality among patients with acute respiratory distress syndrome (ARDS), although positive evidence is reported in more recent randomized clinical trials 113 . Hence, the use of corticosteroids needs to be monitored in the general population as well as in IBD patients with COVID-19 or ARDS. There was a significant level of heterogeneity observed in the pooled analysis of all outcomes such as the risk of COVID-19, COVID-19 hospitalization, and severe COVID-19, except for the mortality analysis. Through the subgroup analysis, we found that the type of IBD might have contributed to the heterogeneity as the heterogeneity decreased or became non-significant following the subgroup analysis based on the type of IBD. The risk of bias was observed to be lesser in our included studies which indicates a good quality of the studies. Our sensitivity analysis, which was done by removing the studies with the lowest weight, revealed the robustness of our findings by yielding a non-differing result from the original results.

Conclusions
The current evidence indicates that UC is significantly associated with a higher risk of COVID-19, COVID-19 hospitalization, and severe COVID-19 compared to non-UC participants. Additionally, CD patients had a significantly lesser risk of severe COVID-19 compared to non-CD patients. However, no significant association was observed between higher risk of COVID-19, COVID-19 hospitalization, severe COVID-19, and COVID-19 mortality among those who had been diagnosed non-specifically with IBD compared to non-IBD patients.